Tomohide Hori, Justin H. Nguyen and Shinji Uemoto

Jacksonville, Florida, USA

Review Article

Progressive familial intrahepatic cholestasis

Tomohide Hori, Justin H. Nguyen and Shinji Uemoto

Jacksonville, Florida, USA

BACKGROUND:Three types of progressive familial intrahepatic cholestasis (PFIC) have been identified, but their etiologies include unknown mechanisms.

DATA SOURCES:A PubMed search on "progressive familial intrahepatic cholestasis" and "PFIC" was performed on the topic, and the relevant articles were reviewed.

RESULTS:The etiologies of the three PFIC types still include unknown mechanisms. Especially in PFIC type 1, enterohepatic circulation of bile acid should be considered. Ursodeoxycholic acid, partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course.

CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear, detailed studies are urgently required. Strategies for more advanced therapies are also needed. These developments in the future are indispensable, especially for PFIC type 1 patients.

(Hepatobiliary Pancreat Dis Int 2010; 9: 570-578)

progressive familial intrahepatic cholestasis; Byler's disease; liver transplantation; steatosis

Introduction

Progressive familial intrahepatic cholestasis (PFIC) refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The natural course of PFIC causes portal hypertension, liver failure, cirrhosis, hepatocellular carcinoma and extrahepatic manifestations. Three types of PFIC have been identified: (i) deficiency of familial intrahepatic cholestasis 1 (FIC1), Byler's disease, as PFIC type 1 (PFIC1); (ii) deficiency of bile salt export pump (BSEP), Byler's syndrome, as PFIC type 2 (PFIC2); and (iii) deficiency of multidrug resistant 3 (MDR3) as PFIC type 3 (PFIC3). Each mutation is related to hepatocellular transport system genes involved in bile formation.[1,2]Although the etiologies of the three types have been demonstrated, they still include unknown mechanisms. Cholestasis is a major clinical sign in all three types. PFIC should be suspected in children with a clinical history of cholestasis of unknown origin after exclusion of the other main causes.[3]A high level of serum bile acid (BA) excludes primary disorders of BA synthesis.[4,5]The phenotypic findings in PFIC1 and PFIC2 are similar, although some slight differences have been identified.[6-11]Extrahepatic features that have been documented in PFIC1 patients, such as persistent short stature, sensorineural deafness, watery diarrhea, pancreatitis, elevated sweat electrolyte concentration and liver steatosis,[5,12]have not been reported in PFIC2. PFIC3 shows some differences from PFIC1 and PFIC2 in disease course.

Historical overview

PFIC refers to a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The actual prevalence remains unknown, but the estimated incidence is one per 50 000-100 000 births. The natural course of PFIC causes portal hypertension, liver failure, cirrhosis, hepatocellular carcinoma and extrahepatic manifestations. Three types of PFIC have been identified.

Manifestations in each type of PFIC

The combined considerations of clinical, biochemical, radiological and histological approaches, including liver immunostaining and biliary lipid analyses, help the diagnosis of PFIC candidates. After a review of previous studies, the etiology and clinical manifestations ofeach type of PFIC documented in these studies are summarized in Table.

Table. Characteristic findings in PFICs

Therapeutic strategies for PFIC

Though therapy with ursodeoxycholic acid (UDCA) is considered during the initial therapeutic management of children with all types of PFIC,[13]more advanced strategies such as cell transplantation, gene therapy or specific targeted pharmacotherapy may represent alternative therapies for all types of PFIC in the future.[14-17]Some patients with PFIC1 or PFIC2 may also benefit from surgical biliary diversion.[18,19]Nasobiliary drainage may help to select potential responders to biliary diversion.[20]The criteria for identifying those PFIC1 and PFIC2 patients who could benefit from UDCA or biliary diversion are unclear.[15,21]Many physicians consider that liver transplantation (LT) is the only alternative if these therapies fail.[22]Although UDCA therapy has advantages, especially for PFIC3, the resultant liver cirrhosis in PFIC patients still requires LT including living donor liver transplantation (LDLT) as a definitive therapy.

PFIC1

Clinical manifestations

PFIC1 patients show a normal level of serum gammaglutamyltransferase (γ-GT). Cholestasis usually appears in the first few months of life, and causes recurrent episodes of jaundice that become permanent later in the course of the disease. Severe pruritus is usually observed. Phenotypic findings and extrahepatic features have been described in PFIC1.[6-12]

Histopathological findings

The hepatic histopathology is characterized by canalicular cholestasis and the absence of true ductular proliferation with only periportal biliary metaplasia of hepatocytes. Histopathological analysis reveals canalicular cholestasis, absence of true ductular proliferation, periportal biliary metaplasia of hepatocytes, pronounced portal/lobular fibrosis, pronounced portal/ lobular inflammation, hepatocellular necrosis, giant cell transformation and perturbed liver architecture.[6,11,12]

Etiology and disease mechanism

PFIC1 is caused by mutations in the ATP8B1 gene (designated FIC1).[9,23]Adenosine triphosphate (ATP) is elaborated from adenosine diphosphate and phosphoric acid via ATPase, and the FIC1 gene, which encodes a P-type ATPase, is located on human chromosome 18. Mutations in this gene have been confirmed in the milder phenotype of benign recurrent intrahepatic cholestasis type 1 (BRIC1) and in Greenland familialcholestasis.[9,23,24]The FIC1 protein is located on the canalicular membrane of hepatocytes, but is mainly expressed in intrahepatic cholangiocytes.[25,26]The function of the P-type ATPase is still unknown. However, it could be an aminophospholipid transporter responsible for maintaining the enrichment of phosphatidylserine and phosphatidylethanolamine on the inner leaflet of the plasma membrane.[9,25]The asymmetric distribution of lipids in the membrane bilayer plays a protective role against high concentrations of bile salt (BS) in the canalicular lumen.[27]The issue of how these mutations cause cholestasis is unclear. It is postulated that abnormal protein function may indirectly disturb the biliary secretion of BA, thus explaining the low concentration of biliary BA.[7,9]Some investigators have reported that impaired FIC1 function results in substantial downregulation of farnesoid X receptor (FXR), a nuclear receptor involved in the regulation of BA metabolism, with subsequent downregulation of BSEP in the liver and upregulation of BA synthesis and the apical sodium BS transporter in the intestine.[26,28,29]Eventually, these events lead to BA overload in hepatocytes (Fig. 1).

Fig. 1. Schema of a possible mechanism in PFIC1.

Fig. 2. Schema of a possible mechanism of enterohepatic circulation in PFIC1.

Furthermore, downregulation of the cystic fibrosis transmembrane conductance regulator in cholangiocytes has been reported in PFIC1, and this downregulation could contribute to the impairment of bile secretion and explain some of the extrahepatic features.[26]The FIC1 gene is expressed in various organs, including the liver, pancreas, small intestine and kidney, but is more highly expressed in the small intestine than in the liver.[23]Therefore, enterohepatic cycling of BS should be considered in the therapies for PFIC1 patients (Fig. 2). This may also explain the digestive symptoms including chronic diarrhea in PFIC1. Other extrahepatic features such as persistent short stature, deafness and pancreatitis suggest a general cell biological function for FIC1.[9,12,30]

PFIC2

Clinical manifestations

PFIC2 patients have normal serum γ-GT activity. Although PFIC1 and PFIC2 share similar laboratory findings, PFIC2 patients have higher serum levels of transaminase and alpha-fetoprotein than PFIC1 patients.[6-12]The initial evolution of cholestasis is more severe than that in the other PFIC types, with permanent jaundice from the first few months of life and rapid appearance of liver failure within the first few years. Severe pruritus is usually observed. Hepatocellular carcinoma may complicate the course before 1 year of age. Since patients with BSEP deficiency accompanied by biallelic truncating mutations have a considerable risk for hepatobiliary malignancy (15% of patients develop hepatocellular carcinoma or cholangiocarcinoma),[31,32]close monitoring of malignancy in PFIC2 patients is justified.

Histopathological findings

The histopathological findings reveal more perturbed liver architecture than PFIC1, with more pronounced lobular and portal fibrosis and inflammation. Canalicular cholestasis, absence of true ductular proliferation, severe lobular injury, more pronounced lobular/portal fibrosis and inflammation, more obvious hepatocellular necrosis, more evident giant cell transformation and more perturbed liver architecture are histopathologically confirmed. Hepatocellular necrosis and giant cell transformation are also much more pronounced in PFIC2 than in PFIC1. These differences between PFIC1 and PFIC2 probably reflect the severe lobular injury in PFIC2.[6,11,12]

Etiology and disease mechanism

PFIC2 is caused by mutations in the ABCB11 gene (designated BSEP).[10,33]The BSEP gene encodes the ATP-dependent canalicular BSEP of the liver and is located on human chromosome 2. The BSEP protein, which is expressed on the hepatocyte canalicular membrane, is the major exporter of primary BA against extreme gradients of concentration. Mutations in this gene are responsible for decreased biliary BS secretion, which leads to decreased bile flow and accumulation of BS inside the hepatocytes, thereby resulting in severe hepatocellular damage (Fig. 3).

PFIC3

Clinical manifestations

PFIC3 patients show a high level of serum γ-GT, a normal level of serum cholesterol and moderately raised concentrations of serum primary BS. PFIC3 can be distinguished from the other types because it rarely presents with cholestatic jaundice in the neonatal period, and instead occurs later in infancy and childhood and even in young adulthood. Pruritus is usually mild, and the evolution of the cholestasis is characterized as chronic icteric or anicteric. However, adolescent and young adult patients have cirrhotic symptoms owing to portal hypertension that may result in liver failure.

Histopathological findings

Fig. 3. Schema of disease mechanism in PFIC2. ADP: adenosine diphosphate.

The liver histopathology obtained at the early phase shows portal fibrosis and true ductular proliferation with a mixed inflammatory infiltrate. Cholestasis in the lobule and some ductules containing bile plugs is also reported.[1]Rare cholestasis, true ductular proliferation, normal interlobular bile ducts, rare extensive portal fibrosis, mixed inflammatory infiltrate, rare biliary cirrhosis and no biliary epithelium injury are partially confirmed. Slight giant transformation of hepatocytes can be observed. Cytokeratin immunostaining confirms strong ductular proliferation within the portal tract. At the later phase, extensive portal fibrosis and a typical picture of biliary cirrhosis are confirmed. Interlobular bile ducts are seen in most portal tracts, and there is neither periductal fibrosis nor biliary epithelium injury.[3]No liver tumors have yet been reported in PFIC3 patients.[34]

Etiology and disease mechanism

PFIC3 is caused by mutations in the ABCB4 gene (designated MDR3) located on chromosome 7. MDR3 is a phospholipid translocase involved in biliary phospholipid (phosphatidylcholine) excretion and is predominantly expressed in the canalicular membrane of hepatocytes.[34]Cholestasis results from toxicity of the bile, in which detergent BSs are not inactivated by phospholipids, thus leading to bile canaliculi and biliary epithelium injuries. The mechanism of the liver damage in PFIC3 is probably related to the absence of biliary phospholipids.[3]The damage to the bile canaliculi and biliary epithelium probably results from continuous exposure to hydrophobic BSs, the detergent effects of which are no longer countered by phospholipids, thus leading to cholangitis.[3]The stability of the mixed micelles in bile requires a proper proportion of BSs, and phospholipids are necessary to maintain the solubility of cholesterol. The absence of phospholipids in bile would be expected to destabilize the micelles and promote the lithogenicity of bile with crystallization of cholesterol, which could favor small bile duct obstruction. These cholangiopathy mechanisms are consistent with thehistopathological findings of ductular proliferation. PFIC3 is an important example of canalicular transport defects that lead to the development of cholangiopathy. A schematic mechanism for PFIC3 is proposed in Fig. 4.

Fig. 4. Schema of disease mechanism in PFIC3. ADP: adenosine diphosphate.

PFIC-like phenotypes

It cannot be negated that other unidentified genes involved in bile formation may be responsible for the PFIC1/2/3 phenotypes. Furthermore, it can be hypothesized that combined heterozygous mutations in MDR3 and BSEP lead to PFIC-like phenotypes.[35]Another possible explanation is that the mutated protein may have a dominant-negative effect on the expression and/or function of the protein in a heterozygous state.[36]Modifier genes and environmental influences could play roles in the expression of PFIC.[4]

FIC1 deficiency

Only one mutated allele or no mutation is identified in a few PFIC patients (<10%).[1]Mutations that may map to regulatory sequences of the genes are a possible explanation for these findings. A gene involved in the transcription of the PFIC genes (i.e. FXR) or in protein trafficking could also be involved.[37,38]

FIC1 disease represents a continuum with intermediate phenotypes between benign recurrent intrahepatic cholestasis type 1 (BRIC1) and PFIC1,[9]and there are no clear explanations for the phenotypic differences between BRIC1 and PFIC1. The mutations in PFIC1 severely disrupt the protein function, whereas the protein function in BRIC1 is only partially impaired.[39]The genotype-phenotype associations are probably complicated, because dramatic variability in the phenotypic presentations has been identified in BRIC1 patients with a common mutation. The FIC1 diseases are compound heterozygous diseases, which further complicate the identification of genotype-phenotype correlations.[39]Heterozygous FIC1 mutations have also been identified in intrahepatic cholestasis of pregnancy type 1.[40,41]

BSEP deficiency

BSEP deficiency represents a phenotypic continuum between BRIC2 and PFIC2. Although no genotypephenotype correlations have been identified among PFIC2 patients, BSEP mutations lead to a lack of canalicular BSEP protein expression, regardless of the mutation type.[8]Severe phenotypes are often associated with mutations leading to premature protein truncation or failure of protein production. Insertion, deletion, nonsense and splicing mutations result in damaging effects, and little or no detectable BSEP at the hepatocyte canaliculus is confirmed. Missense mutations are also common defects that either affect the protein processing and trafficking or disrupt functional domains and the protein structure.[14,31,42]Thus, detectable BSEP expression does not exclude functional BSEP deficiency. Some mutations have been functionally characterized to confirm the defect in BA secretion.[43,44]In milder diseases such as BRIC2,[45]missense mutations predominate over mutations leading to failure of protein production, and mutations tend to occur in less conserved regions rather than in the nucleotidebinding fold. Cholelithiasis has also been reported in BRIC2 patients.[1,45,46]Heterozygous ABCB11 mutations have also been identified in patients with intrahepatic cholestasis of pregnancy type 2.[46-48]

MDR3 deficiency

The phenotypic spectrum of PFIC3 ranges from neonatal cholestasis to cirrhosis in young adults.[3,49]MDR3 gene sequence analyses revealed the presence of different mutations in 60% of PFIC3 patients.[1]Mutations are characterized on both alleles in most cases. In one-third of patients, the mutations give rise to truncated proteins. No MDR3 P-glycoprotein can be detected by immunostaining of the liver.[1]This absence can be explained in two ways. The truncated proteins may be broken down very rapidly after synthesis, thereby giving rise to extremely low steadystate levels. A premature stop codon may also lead to instability and decay of the mRNA of the MDR3 gene. This is supported by the near absence of MDR3 mRNA in the liver.[50,51]The remaining two-thirds of the patients have missense mutations. Some of these occur in the highly conserved amino acid sequences of the Walker A and B motifs.[52]Such amino acid changes are not generally compatible with ATPase activity and transport processes.[52,53]Alternatively, missense mutations may result in intracellular misprocessing of MDR3.[14,54-56]Such missense mutations are associated with decreased levels of canalicular MDR3 protein.[55]Regardless of the mechanism involved, the low level of biliary phospholipids found in PFIC3 with missense mutations demonstrates a functional defect in MDR3.[3]MDR3 defects are currently involved in intrahepatic cholestasis of pregnancy type 3,[56-60]cholesterol gallstone disease,[35,61]drug-induced cholestasis,[62,63]transient neonatal cholestasis and adult idiopathic cirrhosis.[34,49]MDR3 deficiency may also represent a clinical continuum, as a single patient may experience different phenotypes during the disease course.[64]

Actual treatments

UDCA and other therapy

For PFIC1, medication with UDCA is considered during the initial therapeutic management ofchildren.[13]Against the digestive symptoms including pancreatitis in PFIC1 patients, medications with pancreatic enzymes and fat-soluble vitamins are available, if necessary.[65]PFIC patients are theoretically at risk for further development of biliary stones, drug-induced cholestasis and intrahepatic cholestasis of pregnancy during the disease course. Female PFIC patients under UDCA therapy who reach adulthood with their native liver must not stop UDCA during pregnancy because of the risk of developing severe ICP as observed in a previously reported patient who became pregnant.[1,62]

For PFIC2, medication with UDCA is also considered during the initial therapeutic management of children.[13]In PFIC2, it remains uncertain whether hepatocyte transplantation and gene therapy with modified hepatocytes are good therapeutic approaches. Indeed, with these approaches, there may be a risk of leaving premalignant liver cells in place, especially in patients with severe biallelic BSEP gene mutations.[32]

For PFIC3, UDCA therapy may be effective in some patients, especially those with missense mutations who have less severe disease than children with a mutation leading to a truncated protein.[3]

Surgical biliary diversion for PFICs

Previously, partial external biliary diversion (PEBD) has been documented as a surgical procedure for PFIC patients.[66-70]Some patients with PFIC1 or PFIC2 may also benefit from biliary diversion,[18,19]and the surgical procedure of PEBD is usually chosen. Nasobiliary drainage may help to select potential responders to biliary diversion.[20]Although preliminary data suggest that PFIC2 patients with pD482G or pE297G mutations may respond well to biliary diversion,[15]the criteria for identifying those PFIC1 and PFIC2 patients who could benefit from UDCA or biliary diversion are still unclear.[15,21]Many physicians understand that LT is the only alternative if these therapies fail.[22]

LT including LDLT for PFICs

Basically, there are no differences between PFICs and the other end-stage liver diseases in the indications for LT including LDLT. However, more thoughtful considerations are required in LT for PFICs, based on each mechanism.

The possibility of recurrence of PFIC after LT owing to alloimmunization of the recipient against the FIC1, BSEP or MDR3 proteins of the liver donor remains a theoretical matter of debate.[1]It is hypothesized that PFIC patients with a severe mutation leading to the absence of the gene product would be immunologically naive for the FIC1, BSEP or MDR3 gene products. Moreover, alloimmunization necessarily occurs after LT. Although evidence regarding this hypothesis has not been reported,[22,71]a case of a PFIC2 patient who experienced an unexplained severe bout of pure hepatocellular cholestasis resembling PFIC2 after deceased donor LT has been reported.[1]In the case of LDLT based on donor relationships with parents, it can be expected that the heterozygous status of the liver allograft leads to a predisposition for developing lithiasis or cholestasis favored by immunosuppressive drugs[47]that may interfere with canalicular protein function, as reported in a PFIC2 patient.[1]This possibility may be very rare as there is only one previous report.[1]

For PFIC1 patients, thoughtful considerations are required for the introduction of LT.[65]The extrahepatic features such as diarrhea, liver steatosis and short stature that are sometimes associated with PFIC1 do not improve or may be aggravated after successful biliary diversion or LT.[1,12]A single-center experience of LDLT for PFIC1 with long-term follow-up has been reported.[65]The steatosis/steatohepatitis in the early period after LDLT, and recurrences of digestive symptoms are documented.[65,72]Liver steatosis and diarrhea may occur even after retransplantation.[1]Chronic diarrhea may become intractable when biliary BS secretion is restored after LT,[9,12,30]while diarrhea may be favorably managed by bile adsorptive resin treatment.[12,30]The clinical courses of PFIC1 recipients after LT are still not sufficient, based on previous reports.[65,72]Previous reports for the early postoperative occurrence of steatosis and fibrosis may oblige us to challenge some other therapies for PFIC1 patients. Since expression of the FIC1 gene occurs in several organs, and enterohepatic circulation of BA should be involved in PFIC1, the impact of a malfunction of the ATP8B1 product upon the steatosis/steatohepatitis after LDLT has been suggested.[65]The usefulness of bile acid adsorptive resin for bile acid diarrhea and growth retardation in PFIC1 recipients has been reported.[30]

PFIC2 patients are good candidates for LT. Extrahepatic features that have been documented in PFIC1 patients, such as persistent short stature, sensorineural deafness, watery diarrhea, pancreatitis, elevated sweat electrolyte concentration and liver steatosis,[12]have not been reported in PFIC2. Our data and a review of the previous studies[1,22]that have demonstrated that PFIC2 is indicated for LT including LDLT, as a definitive therapy, similar to other diseases indicated for LT. PFIC2 patientsseem to be good candidates for LT.

In PFIC3, LT is required at a mean age of 7.5 years,[1]and some previous reports have documented PFIC3 patients who underwent LDLT.[73,74]PFIC3 patients require LT owing to the progression of cirrhosis during a long period,[75]similar to the case for the other recipients who undergo LT because of advanced cirrhosis.

Conclusion

This review attempts to summarize the current status of hypothetical mechanisms and therapeutic strategies for PFIC patients. To the present, the etiology and disease mechanism in PFICs are still unclear. So, detailed studies of the etiology and disease mechanism are urgently required. Established strategies of more advanced therapies are also needed. These developments in the future are indispensable, especially for PFIC1 patients. This review indicates a path for further improvement of the clinical courses in PFIC patients.

Funding:None.

Ethical approval:Not needed.

Contributors:HT wrote the main body of the article under the supervision of US. NJH and US provided advice on medical aspects. HT is the guarantor.

Competing interest:No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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May 7, 2010

Accepted after revision August 21, 2010

Author Affiliations: Department of Neuroscience (Hori T) and Division of Transplant Surgery, Department of Transplantation (Nguyen JH), Mayo Clinic in Florida, Jacksonville, fl32224, USA; Divisions of Hepato-Biliary-Pancreatic, Pediatric and Transplant Surgery, Department of Surgery, Kyoto University Hospital, Sakyo-ku, Kyoto 606-8507, Japan (Uemoto S)

Tomohide Hori, MD, PhD, Department of Neuroscience, Birdsall Research Bldg., 3rd. Fl., Rm 323, Mayo Clinic in Florida, 4500 San Pablo Rd., Jacksonville, fl32224, USA (Tel: +1-904-953-2449; Fax: +1-904-953-7117; Email: hori.tomohide@mayo.edu)

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.